Received for publication March 28, 2006.
Revised May 11, 2006.
Accepted for publication May 12, 2006.

Pharmacological characterization of hydrolysis-resistant analogs of oleoylethanolamide with potent anorexiant properties

Abstract

Oleoylethanolamide (OEA) is an endogenous lipid mediator that reduces food intake, promotes lipolysis and decreases body-weight gain in rodents by activating peroxisome proliferator-activated receptor type- (PPAR-) (Rodriguez de Fonseca et al., 2001; Fu et al., 2003; Guzman et al., 2004; Nielsen et al., 2004; Proulx et al., 2005). The biological effects of OEA are terminated by two intracellular lipid hydrolase enzymes, fatty-acid amide hydrolase (FAAH) (Desarnaud et al., 1995; Cravatt et al., 1996) and N-acylethanolamine-hydrolyzing acid amidase (NAAA) (Tsuboi et al., 2005; Ueda et al., 2005). In the present study, we describe OEA analogs that resist enzymatic hydrolysis, activate PPAR- with high potency in vitro, and persistently reduce feeding when administered in vivo either parenterally or orally. The most potent of these compounds, (Z)-(R)-9-octadecenamide,N-(2-hydroxyethyl,1-methyl) (KDS-5104), stimulates transcriptional activity of PPAR- with a half-maximal effective concentration (EC₅₀) of 100±21 nM (n = 11). Parenteral administration of KDS-5104 in rats produces persistent, dose-dependent prolongation of feeding latency and post-meal interval (PMI) (half-maximal effective dose, ED₅₀ = 2.4±1.8 mg kg^-1, intraperitoneal, i.p.; n = 18), as well as increased and protracted tissue exposure compared to OEA. Oral administration of the compound also results in a significant tissue exposure and reduction of food intake in free-feeding rats. These results suggest that the endogenous high-affinity PPAR- agonist OEA may provide a scaffold for the discovery of novel orally active PPAR- ligands.

Key words: OEA, PPAR, fatty acid ethanolamide, feeding, food intake, peroxisome proliferator-activated receptor